Drug-resistant bacterial infections and related morbidity and mortality are on the rise around the world. In particular the so-called “ESCAPE” pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter ssp) are the causative agents for the majority of hospital infections and effectively “escape” the effects of approved drugs (Clinical Infectious Diseases 2010; 50: 1081).
Because of world-wide mortality due to uncontrolled severe infections is on the rise, the need for new antimicrobial compounds becomes greater every day. The limited number of targets for antibiotic action, development of multi-drug resistant strains and the ever shrinking number of active drugs have increased the health risks of the human race with respect to the number one killer of all people in the world today, bacterial infection. With the identification of New Delhi metallo-beta-lactamase-1 (NDM1), and highly drug resistant gonorrhoeal strains new antibiotics become more essential on a daily basis.
New classes of antibiotics are being continuously developed, with limited success, in order to expand the armamentarium of treatment options against severe bacterial infections. For instance, second generation quinolones such as Ciprofloxacin are widely accepted for the treatment of bacterial infections of respiratory and urinary tract, skin and soft tissues. Such compounds have good pharmacokinetic profiles, potent activities against a wide range of Gram-positive and Gram-negative pathogens, and are widely used in both hospital and community settings. However, increasing frequency of bacterial resistance to quinolones, among other currently available antibiotics, has led to an urgent need for new analogs to overcome antibiotic resistance.
Bacterial type II topoisomerases are key regulators of the replication, repair and decatenation of DNA in bacteria and are clinically validated targets for antibacterial agents, as demonstrated by the clinical and commercial success of quinolones for the treatment of bacterial infections. Nalidixic acid, introduced in 1962, is considered to be the predecessor of all members of the quinolone family, including the second (e.g. Ciprofloxacin), third (e.g. Levofloxacin) and fourth (e.g. Moxifloxacin) generations commonly known as fluoroquinolones. These molecules form a ternary complex consisting of the inhibitor, topoisomerase and DNA that disrupts DNA replication and repair as well as RNA transcription, a two-punch combination that leads to rapid bacterial cell death. Several compound- and DNA-bound enzyme structures have been solved, paving the way for a greater understanding of both the mechanism for DNA cleavage and the structural basis for inhibition of topoisomerases by antibacterial compounds. Recently, the X-ray crystal structures of the quinolone binding mode have appeared (Bax et al., 2010), generating opportunities for structural optimization and design of topoisomerase inhibitors.
2-Pyridones are a class of antibiotics which inhibit type IIa bacterial topoisomerases and are chemically bioisosteres of quinolones. In 1994, Abbott reported that 2-pyridone analogs were efficacious against certain quinolone resistant microorganisms (34th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC, paper F41), 1994; U.S. Pat. No. 5,789,591), specifically ABT-719, a 4-oxo-quinolizine possessing potent antibacterial activity against both Gram-positive and Gram-negative pathogens. See also Sato U.S. Pat. Nos. 6,525,066 and 7,223,773.
The continuing development of natural and engineered resistance to antibiotics in use today necessitates the development of ever new classes of antibiotic compounds which are potent, safe and do not exhibit cross-resistance to existing classes of antibiotics. Furthermore, such compounds would have broad spectrum for empirical first-line treatment, have antibacterial activity via inhibition of bacterial type II topoisomerases, e.g. DNA gyrase (Topo 11) and topoisomerase IV (Topo IV), and would preferably be orally bioavailable.